This project involves the conduct of a therapeutic clinical trial using autologous blood stem cell gene therapy to treat X-linked severe combined immune deficiency. Gene therapy can restore immunity to infants with X-linked severe combined immunodeficiency (XSCID) caused by mutations in the IL2RG gene encoding the common gamma chain (gc) of receptors for interleukins (IL)-2, -4, -7, -9, -15 and -21. Our goal is to investigate the safety and efficacy of gene transfer treatment as salvage treatment for older XSCID children with inadequate immune reconstitution despite prior bone marrow transplant(s). In our now closed earlier protocol that provided background to the current lentivector protocol, we used gamma-retroviral vector to mediate the gene transfer without any conditioning regimen, which did not achieve sustained correction and expansion of the genetically corrected lymphoid cells. We have in April 2016 published the first report of the first five of six older subjects with partially corrected X-SCID, treated using a integrating lentivector mediated gene transfer combined with mild/moderate dose of busulfan 6mg/kg total for myeloconditioning (De Ravin SS, et al. Sci Transl Med April 2016) that is the major scientific accomplishment for this report. This vector is developed in collaboration with extramural investigators (Dr Brian Sorrentino) at St Jude Children's Research Hospital, Memphis. We have now treated eight patients in total, and to date, no serious adverse events related to the gene therapy have been observed. Significant levels of myeloid gene marking is observed, and in patients with sufficient length of follow-up, the gene marking in T and B cells continues to improve, with associated clinical benefits. With the exception of the two most recently treated patients, all of them have eradicated their chronic norovirus. Analysis of the transgene integration continues to show polyclonal integration patterns, without any growing dominance of any particular clones.